The influence of stroma cells on the generation and function of FoxP3- expressing regulatory T cells in the intestinal immune system
Final Report Abstract
Regulatory T cells (Tregs) are important cellular mediators of tolerance to food antigen. Treg induction in the gut-draining mesenteric lymph nodes (mLN) requires antigen presentation by dendritic cells in the presence of transforming growth factor (TGF)-β and vitamin A metabolite retinoic acid (RA). Using a murine lymph node (LN) transplantation model, we have previously shown that RA production by non-hematopoietic stromal cells confers the unique ability of mLN to induce gut homing receptors on lymphocytes. The aim of this study was to investigate whether mLN stromal cells are also responsible for the preferential generation of Treg in mLN. Through transplantation of mLN or skin-draining peripheral lymph nodes (pLN) to the site of an excised pLN, we generated chimeric LNs, in which only the non-hematopoietic cells were of donor origin. Thus, we established that the enhanced capacity of mLN to support Treg generation was an intrinsic property of the LN which was imprinted into the structural cells of the LN and retained in a different environment. Using in-vitro co-culture experiments, we corroborated the superior ability of mLN stromal cells to support Treg induction. Intriguingly, however, this ability of mLN stromal cells did not rely on RA production but correlated with the expression of TGF-β-activating integrin β8. Moreover, microarray analysis showed that stromal cells in mLN and pLN differentially affected gene expression in dendritic cells, suggesting that stromal cells modulate T cell immune responses directly as well as indirectly via effects on dendritic cells. To identify factors which shape site-specific properties of LN stromal cells, we depleted mice of vitamin A using a special diet. Interestingly, vitamin A depletion reduced the propensity of liver-draining celiac LNs, but not that of mLN, to support Treg induction. Instead, we identified the microbiota as an important factor shaping mLN-specific stromal cell function. Furthermore, we used LN transplantation to the site of the excised mLN to identify molecular mediators of stromal cell-specific function. Interleukin (IL)-6, which is expressed at higher levels in pLN compared to mLN, was not a factor determining the differential ability of pLN and mLN to generate Tregs and did not affect T cell polarization. Intriguingly, however, we found that the generation of immunoglobulin (Ig)-A+ plasma cells was impaired in LNs lacking IL6 in stromal cells. Finally, we found that stromal cells had a decisive effect not only on Treg induction, but also on the size of the T cell pool. Under pro-inflammatory conditions, stromal cells restrained T cell expansion in a manner depending on interferon-γ receptor expression. Collectively, our work shows that stromal cells in different LNs are stably imprinted with sitespecific properties and that they actively modulate T cell polarization as well as the size of the T cell pool. Our findings add to a growing body of evidence placing stromal cells at the center of immune response induction.
Publications
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Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011 Feb 25;34(2):237-46
Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, Müller W, Sparwasser T, Förster R, Pabst O
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Oral tolerance to food protein. Mucosal Immunol. 2012 May;5(3):232-9
Pabst O., Mowat AM
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Antigen sampling in the small intestine. Trends Immunol. 2013 Apr;34(4):155-61
Schulz O, Pabst O
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On the road to tolerance--generation and migration of gut regulatory T cells. Eur J Immunol. 2013 Jun;43(6):1422-5
Pabst O, Bernhardt G
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Trafficking of regulatory T cells in the intestinal immune system. Int Immunol. 2013 Mar;25(3):139-43
Pabst O
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The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. Mucosal Immunol. 2014 Mar;7(2):359-68
Cording S, Wahl B, Kulkarni D, Chopra H, Pezoldt J, Buettner M, Dummer A, Hadis U, Heimesaat M, Bereswill S, Falk C, Bode U, Hamann A, Fleissner D, Huehn J, Pabst O
